Performance Evaluation of the BACTEC MGIT 960 System for Rifampin Drug-Susceptibility Testing of Mycobacterium tuberculosis Using the Current WHO Critical Concentration.

The World Health Organization recently lowered the rifampin (RIF) critical concentration (CC) for drug-susceptibility testing (DST) of Mycobacterium tuberculosis complex (MTBC) using the mycobacterial growth indicator tube (MGIT) 960 system. Here, we evaluated the diagnostic performance of the MGIT system with the revised CC for determining MTBC RIF resistance with 303 clinical MTBC isolates, including 122 isolates with rpoB mutations, of which 32 had single borderline-resistance mutations, and 181 wild-type rpoB isolates. The phenotypic RIF resistance was determined via the absolute concentration method (AC) and via MGIT using both previous (1 mg/L) and revised (0.5 mg/L) CCs for the latter method. The diagnostic accuracy of each phenotypic DST (pDST) was assessed based on rpoB genotyping as the reference standard. The overall sensitivity of the AC was 95.1% (95% confidence interval [CI], 89.6 to 98.2%), while the MGIT results with previous and revised CCs were 82.0% (95% CI 74.0 to 88.3%) and 83.6% (95% CI 75.8 to 89.7%), respectively. The 32 MTBC isolates with single borderline-resistance mutations showed a wide range of MICs, and sensitivity was not significantly increased by reducing the MGIT CC. All 181 wild-type rpoB isolates were RIF-susceptible in the AC and with MGIT using the previous CC, whereas 1 isolate was misclassified as RIF-resistant with the revised CC. Our results demonstrate that the overall diagnostic performances of the MGIT DST with the revised RIF CC and previous CC were comparable. A further large-scale study is required to demonstrate the optimal RIF CC for MGIT.

Mutations in gyrA and gyrB in Moxifloxacin-Resistant Mycobacterium avium Complex and Mycobacterium abscessus Complex Clinical Isolates.

Data on the frequency of gyrA and gyrB mutations in fluoroquinolone-resistant isolates of the Mycobacterium avium complex (MAC) and the Mycobacterium abscessus complex (MABC) are limited. In our analysis, we did not find any resistance-associated mutations in gyrA or gyrB in 105 MAC or MABC clinical isolates, including 72 moxifloxacin-resistant isolates. Our findings suggest that mechanisms other than gyrA and gyrB mutations contribute to moxifloxacin resistance in these organisms.

Limited Effect of Later-Generation Fluoroquinolones in the Treatment of Ofloxacin-Resistant and Moxifloxacin-Susceptible Multidrug-Resistant Tuberculosis.

Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant, moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used for all patients. Overall, 171 patients (82%) had ofloxacin-susceptible, moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group), and 37 (18%) had ofloxacin-resistant, moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a history of MDR-TB treatment (P < 0.001) and cavitary lesions on chest radiography (P < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have resistance to the drugs pyrazinamide (P = 0.003), streptomycin (P = 0.015), prothionamide (P < 0.001), and para-aminosalicylic acid (P < 0.001). Favorable outcomes were more frequently achieved for the ofloxacin-susceptible group than for the ofloxacin-resistant group (91% [156/171] versus 57% [21/37], respectively [P < 0.001]). In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval, 1.55 to 18.53) times more likely than the ofloxacin-resistant group (P < 0.001) to have favorable outcomes. Despite in vitro moxifloxacin susceptibility, the frequency of favorable treatment outcomes for ofloxacin-resistant MDR-TB was significantly lower than that for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more-aggressive therapies may be needed for ofloxacin-resistant MDR-TB.

Clinical Characteristics and Treatment Outcomes of Patients with Acquired Macrolide-Resistant Mycobacterium abscessus Lung Disease.

Macrolide antibiotics are mainstays in the treatment of lung disease due to the Mycobacterium abscessus complex. Although previous studies have reported development of acquired macrolide resistance in this species, limited data are available on the outcomes of lung disease due to macrolide-resistant Mycobacterium abscessus subsp. abscessus This study evaluated the clinical features, treatment outcomes, and molecular characteristics of macrolide-resistant isolates of M. abscessus subsp. abscessus We performed a retrospective review of medical records and genetic analysis of clinical isolates from 13 patients who had acquired macrolide-resistant M. abscessus subsp. abscessus lung disease between November 2006 and March 2016. Eleven (85%) patients had the nodular bronchiectatic form of the disease, and two (15%) patients had the fibrocavitary form. When acquired macrolide resistance was detected, 10 (77%) patients were on antibiotic therapy for M. abscessus subsp. abscessus, and three (23%) patients were on therapy for lung disease due to other nontuberculous mycobacteria. The median treatment duration after detecting resistance was 24.0 months (interquartile range, 16.0 to 43.0 months). Treatment outcomes were poor, and final sputum culture conversion was achieved in only one (8%) patient, after resectional surgery. All 13 clinical isolates demonstrated point mutations at position 2058 (n = 10) or 2059 (n = 3) of the 23S rRNA gene, which resulted in acquired macrolide resistance. This study indicates that treatment outcomes are very poor after the development of acquired macrolide resistance in patients with M. abscessus subsp. abscessus lung disease. Thus, more effective measures are needed to prevent development and effectively treat macrolide-resistant M. abscessus subsp. abscessus lung disease.

Mycobacteriological characteristics and treatment outcomes in extrapulmonary Mycobacterium abscessus complex infections.

OBJECTIVES: The differentiation between Mycobacterium abscessus subspecies abscessus (M. abscessus) and Mycobacterium abscessus subspecies massiliense (M. massiliense) and determination of the presence of inducible resistance to macrolide antibiotics are important factors in the management of patients with Mycobacterium abscessus complex (MABC) infections. Unlike pulmonary MABC infections, little information on extrapulmonary MABC infections is available. METHODS: The molecular identification of clinical isolates was performed, and the clinical characteristics and treatment outcomes of 20 consecutive patients with extrapulmonary MABC infections were assessed. RESULTS: M. abscessus and M. massiliense each caused 10 (50%) of the cases. Eight (80%) M. abscessus isolates that had inducible resistance to clarithromycin harbored an intact erm(41) gene of the T28 variant, whereas two (20%) M. abscessus isolates had the C28 erm(41) variant and were susceptible to clarithromycin. All M. massiliense isolates had a truncated erm(41) gene and were susceptible to clarithromycin. The drug susceptibility profiles other than clarithromycin were similar for the M. abscessus and M. massiliense isolates. Of the 20 patients, 17 (85%) showed a favorable outcome, including all patients with M. massiliense infection and 70% (7/10) of patients with M. abscessus infection. Favorable outcomes were associated with M. massiliense and M. abscessus isolates with a non-functional erm(41) gene (p=0.049). CONCLUSIONS: Precise species and subspecies identification and the determination of macrolide susceptibility are recommended for the optimal treatment of extrapulmonary MABC infections.

Treatment Outcomes with Fluoroquinolone-Containing Regimens for Isoniazid-Resistant Pulmonary Tuberculosis.

Resistance to isoniazid (INH) is the most common form of drug resistance in pulmonary tuberculosis (TB). Although fluoroquinolones (FQs) are recommended to strengthen treatment regimens for INH-resistant pulmonary TB, few studies have evaluated the clinical efficacy of FQ-containing regimens in patients with INH-resistant pulmonary TB. A retrospective cohort study of 140 patients with INH-resistant pulmonary TB was performed between 2005 and 2012. We evaluated whether FQ-containing regimens yielded improved treatment outcomes for patients with INH-resistant pulmonary TB. Overall, favorable outcomes were achieved in 128 (91.4%) patients. Unfavorable outcomes occurred in 12 patients (8.6%), including 7 with treatment failure (5.0%) and 5 with relapse after initial treatment completion (3.6%). FQs, such as levofloxacin and moxifloxacin, were given to 75 (53.6%) patients. Favorable treatment outcomes were more frequent for patients who received FQs (97.3% [73/75 patients]) than for those who did not receive FQs (84.6% [55/65 patients]) (P = 0.007). Patients who did not receive FQs were more likely to develop treatment failure (9.2% [6/65 patients] versus 1.3% [1/75 patients]) (P = 0.049) than patients who received FQs. The adjusted proportion of unfavorable outcomes was significantly higher among patients who did not receive FQs (8.8%; 95% confidence interval [CI], 3.3 to 21.5%) than among those who did receive FQs (1.5%; 95% CI, 0.3 to 7.7%) (P = 0.037). These results suggest that the addition of FQs can improve treatment outcomes for patients with INH-resistant pulmonary TB.

Clinical Features and Treatment Outcomes of Bloodstream Infections Caused by Extended-Spectrum ß-Lactamase-Producing Escherichia coli Sequence Type 131.

Despite the remarkable emergence of extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli sequence type 131 (ST131), the clinical features and outcomes of infections caused by ST131 remain poorly described. From 2011 to 2012, we collected ESBL-producing E. coli isolates from patients with bloodstream infections in 13 hospitals in Korea and compared clinical characteristics and outcomes between ST131 and non-ST131 clones. Of the 110 ESBL-producing isolates, the most common ST was ST131 (30.9%). Multivariate analysis showed that recent operation was the only variable associated with the ST131 clone; other comorbid conditions and clinical features were similar between ST131 and non-ST131 clones. CTX-M-14 and CTX-M-15 were the predominant types of ESBLs, and CTX-M-15 was significantly associated with ST131. The rate of nonsusceptibility to ciprofloxacin was higher in ST131 than in non-ST131 clones (94.1% vs. 75.0%). No significant differences in 30-day mortality rates were found between ST131 and non-ST131 clones. Multivariate analysis revealed that older age (odds ratio [OR]=5.39, 95% confidence interval [CI] 1.22-23.89; p=0.027), nosocomial infection (OR=4.81, 95% CI 1.15-20.15; p=0.032), and higher Pitt bacteremia score (OR=7.26, 95% CI 1.41-37.42; p=0.018) were independent risk factors for 30-day mortality. The ESBL-producing E. coli ST131 clone has emerged and disseminated in Korea. Our findings reveal similarities in clinical and demographic characteristics between ST131 and non-ST131 clones. Although a more resistant profile has been detected in ST131, patients with the ST131 clone did not exhibit a higher mortality rate.

Mycobacterium chelonae infections associated with bee venom acupuncture.

We report 3 cases of Mycobacterium chelonae infections after bee venom acupuncture. All were treated with antibiotics and surgery. Mycobacterium chelonae infections should be included in the differential diagnosis of chronic skin and soft tissue infections following bee venom acupuncture.

Can levofloxacin be a useful alternative to trimethoprim-sulfamethoxazole for treating Stenotrophomonas maltophilia bacteremia?

A retrospective study was conducted to evaluate the efficacy of levofloxacin in the treatment of Stenotrophomonas maltophilia bacteremia. The 30-day mortality rates were similar between the trimerthoprim-sulfamethoxazole (TMP-SMX) and levofloxacin treatment groups. Adverse events related to antibiotics occurred more frequently in patients receiving TMP-SMX, and recurrent bacteremia due to levofloxacin-resistant S. maltophilia strains developed in patients treated with levofloxacin. Our data suggest that levofloxacin can be a useful alternative option for treating S. maltophilia infections.

Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients.

RATIONALE: The optimal therapeutic regimen and duration of treatment for Mycobacterium abscessus lung disease is not well established. OBJECTIVES: To assess the efficacy of a standardized combination antibiotic therapy for the treatment of M. abscessus lung disease. METHODS: Sixty-five patients (11 males, 55 females, median age 55 yr) with M. abscessus lung disease were treated with clarithromycin, ciprofloxacin, and doxycycline, together with an initial regimen of amikacin and cefoxitin for the first 4 weeks of hospitalization. MEASUREMENTS AND MAIN RESULTS: Treatment response rates were 83% for symptoms and 74% for high-resolution computed tomography. Sputum conversion and maintenance of negative sputum cultures for more than 12 months was achieved in 38 (58%) patients. These rates were significantly lower in patients whose isolates were resistant to clarithromycin (17%, 2/12) compared with those whose isolates were susceptible or intermediate to clarithromycin (64%, 21/33; P = 0.007). Neutropenia and thrombocytopenia associated with cefoxitin developed in 33 (51%) and 4 (6%) patients, respectively. Drug-induced hepatotoxicity occurred in 10 (15%) patients. Because of these adverse reactions, cefoxitin was discontinued in 39 (60%) patients after treatment for a median of 22 days. CONCLUSIONS: Standardized combination antibiotic therapy was moderately effective in treating M. abscessus lung disease. However, frequent adverse reactions and the potential for long-duration hospitalization are important problems that remain to be solved.

Clinical implications of vancomycin-resistant Enterococcus faecium (VRE) with VanD phenotype and vanA genotype.

OBJECTIVES: To investigate the clinical implications of vancomycin-resistant Enterococcus faecium (VRE) with VanD phenotype and vanA genotype (VanD-vanA VRE). METHODS: We tested in vitro and in vivo efficacies of teicoplanin against VanD-vanA VRE strains. Change in teicoplanin MICs was monitored during incubation with teicoplanin. In vitro and in vivo time-kill assay and survival analysis using a mouse peritonitis model were performed. RESULTS: Teicoplanin MICs of VanD-vanA VRE strains increased to 128 mg/L within 48 h when they were cultured with 120 mg/L teicoplanin. In vitro and in vivo time-kill assay showed that VanD-vanA VRE strains were not eliminated by 120 mg/L teicoplanin in contrast to vancomycin-susceptible E. faecium and VanD-vanB strains. The survival rate of mice infected with VanD-vanA VRE strains treated with teicoplanin was comparable with that of untreated mice. CONCLUSION: Data suggest that teicoplanin would fail in the treatment of VanD type VRE infections if the strains contained the vanA gene, which cannot be detected in the clinical microbiology laboratory.

Evaluation of a triple-drug combination for treatment of experimental multidrug-resistant pneumococcal meningitis.

To evaluate the therapeutic efficacy of ceftriaxone + vancomycin + rifampicin (CVR) in the treatment of pneumococcal meningitis caused by a multidrug-resistant strain, single-drug regimens (ceftriaxone 100 mg/kg, rifampicin 15 mg/kg, or vancomycin 20 mg/kg), double-drug regimens (ceftriaxone + vancomycin [CV] and ceftriaxone + rifampicin [CR]) and a triple-drug combination (CVR) with or without dexamethasone were compared in a rabbit meningitis model. Meningitis was induced by a highly penicillin-resistant (MIC 2 mg/l) and ceftriaxone-resistant (MIC 4 mg/l) pneumococcal strain. Final therapeutic efficacy was evaluated by the bacterial concentration at 24 h, and the bacterial killing rate was also evaluated. All combination regimens were superior to ceftriaxone or vancomycin single-drug regimens with regard to sterilisation of CSF and bacterial killing rate. Rifampicin was as effective as combination regimens. Regardless of dexamethasone, therapeutic efficacy of CVR and CR were superior to that of CV. CVR showed comparable therapeutic efficacy to CR. Data suggested that CVR would not have additional therapeutic benefit over CR during the initial 24 h of treatment.